Alzheimer's disease (AD) is on the verge of becoming a worldwide public health crisis. As life expectancy increases, the number of AD cases is expected to increase from 35 million today to more than 115 million by 2050. Currently only two classes of drugs are approved for symptomatic treatment of AD, and there are no approved disease-modifying treatments. A serious impediment to the development of AD therapies is the lack of adequate rodent models for pre-clinical testing. There are two major deficiencies of current transgenic mouse models of AD: 1) the failure to recapitulate the complete disease phenotype, and 2) the failure to incorporate mixed pathologies or co-morbidities that occur in approximately half of individuals with a clinical diagnosis of AD. The proposed project is an attempt to create a more complete transgenic mouse model of AD, in which AD-linked mutations in -amyloid (A) drive pathological changes in wild-type human tau, leading to neurodegeneration and severe cognitive deficits. Such a model is essential for pre-clinical testing of potential therapies for the prevention of symptomatic AD. In addition to the hallmark neuropathological lesions of AD, amyloid plaques and neurofibrillary tangles, abnormal inclusions composed of aggregated a-synuclein and ubiquitinated TAR DNA-binding protein 43 (TDP-43) have been observed in a substantial number of individuals with AD. We hypothesize that AD is a polyproteinopathy in which A, tau, a-synuclein, and possibly TDP-43 act additively or synergistically to impair cognition and cause neurodegeneration. As the initial step in testing this hypothesis, we propose to create transgenic mice that express human APP with an AD- linked mutation, wild-type human tau, and wild-type a-synuclein, in various proportions. We will 1) determine the effect of a-synuclein on levels of A40, A42 and human tau; 2) determine the effect of a-synuclein on amyloid load and neurofibrillary pathology; 3) determine the effect of a-synuclein on neurodegeneration; and 4) determine the effect of a-synuclein on cognitive function, by comparing the phenotypes of bigenic mice expressing APP and tau transgenes to the phenotypes of transgenic mice expressing all three transgenic proteins (APP, tau, a-synuclein). Regardless of etiology, the likelihood of clinical dementia is significantly greater in persons who have mixed pathology than in individuals with plaques and tangles alone. There is therefore concern that the effects of new Alzheimer therapies that are initially tested in mouse models and humans with pure AD may differ when they are dispensed to the general population. The development of mouse models of AD that incorporate mixed pathologies would represent a significant advancement that is likely to increase the predictive validity of pre-clinical studies in mice.